Despite the major advances in clinical cancer therapy due to alkylating agents, drugs of this class have severe limitations. The major problem is one of nonspecific toxicity. There have been numerous attempts to develop alkylating agents which are selectively targeted to tumor cells. With few exceptions the results have been uniformly discouraging. For example, alkylating agents which are activated by .enzymes present in tumor tissue such as alkaline phosphatase, azo-reductase, glucuronidase, plasmin, and collagenase have been explored.
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The fundamental problem remains one of tumor specificity. Although the tumor may have many fold higher levels of the target enzyme normal tissues also invariably possess some of the enzyme which ultimately activates the alkylating agent and results in toxicity. This severely limits tumor selectivity.
In order to circumvent these problems a new class of tumor selective antineoplastic agents was developed. Antineoplastic Drugs with Bipolar Toxification/Detoxification Functionalitites, A. Glazier, (1993) U.S. Pat. No. 5,274,162. These novel antineoplastic agents have two key functionalities: a trigger which toxifies the drug; and an deactivator which detoxifies the drug. The trigger is selected such that it is activated by an enzyme which is present in elevated levels in the tumor. The deactivator is selected such that it is actuated by an enzyme ubiquitous to all tissues. The fate of the drug in a given cell is then determined by the ratio of the enzymatic activity that triggers toxication to the enzymatic activity which detoxifies the drug. The partitioning of the drug between toxic metabolite and nontoxic metabolite defines the resulting specificity of cytotoxic effect. U.S. Pat. No. 5,274,162. by A. Glazier describes a new class of antineoplastic drugs designed to be selectively toxic for tumor cells bearing the enzyme guanidinobenzoatase.
A fundamental characteristic of malignant cells is tissue invasiveness. In order for malignant cells to multiply and spread the cells must degrade the extracellular matrix. An extensive body of scientific data exists which details the crucial role of tumor associated proteases in the processes of malignancy. Tumor associated enzymes implicated in the degradation of the tumor extracellular matrix include: urokinase; tissue plasminogen activator, Cathepsin B; Cathepsin C; Cathepsin D; plasmin; collagenase; Type IV collagenase; and stromelysin.
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Substantial effort has been directed towards the development of inhibitors to these tumor associated proteases as potential anticancer drugs to slow tumor invasion and growth. DeClerck Y A; Imren S; Eur J Cancer (1994) 30A(14):2170-80. However, inhibitors to tumor associated proteases are not lethal to tumor cells and at best would be expected to only slow tumor growth.